PROJECT/CORE: Administrative Core A Project/Core Leader Name: John Q. Trojanowski, MD, PhD Project Summary/Abstract Core A is the Administrative Core of this re-submitted application for a U19 ?Center On Alpha-synuclein Strains In Alzheimer Disease & Related Dementias? at the University of Pennsylvania (Penn) Perelman School of Medicine (PSOM). It facilitates accomplishing the goals of this multidisciplinary research program to elucidate mechanisms of progressive neurodegeneration mediated by different strains of pathological alpha- synuclein (aSyn) underlying cognitive impairments in Alzheimer's disease (AD) and related dementias or ADRD including Lewy body (LB) diseases (LBD) such as dementia with LBs (DLB) and Parkinson's disease without (PD) or with dementia (PDD). Among ADRD, AD with abundant LB co-pathology is the most common subtype of AD. Hence, AD with aSyn LB (AD+LB), PDD and DLB together represent the most common forms of aging related dementias. Thus, the overall goals of this new Penn AD and LBD U19 Center are to elucidate mechanisms of pathological aSyn mediated progressive neurodegeneration in AD+LB versus pure AD (AD-LB) compared with LBD as a function of aging and the heterogeneous accumulations of aSyn, tau and A? pathologies that influence different clinical manifestations of these disorders. We hypothesize that accumulations of pathological aSyn lead to neuron dysfunction and death due to misfolding and transmission of different strains of pathological aSyn to form LBs and LNs compared to those aSyn strains underlying multiple system atrophy (MSA) characterized by glial cytoplasmic inclusions (GCI) since the MSA aSyn strain rarely induces comorbid AD pathology and dementia rarely occurs in MSA patients. Specifically, we pursue the cross-Center shared goal to correlate deep phenotypic data from Projects III/IV directly with strain data generated in Projects I/II in collaboration with the Cores to determine for the first time the correspondence of clinicopathological phenotypes with the novel aSyn strains defined by our preliminary data summarized in each Project (see also Fig. 1 and 2 in the ?Overall Component?). To accomplish its goals, Core A will implement the following Aims: oversee budgetary and fiscal aspects of this U19 Center and guide the progress of the Cores and Projects; promote/foster interactions between Cores and Projects, as well as interactions of Penn U19 investigators with scientists outside the Penn U19 Center at and beyond Penn; serve as an information resource for the patient community and general public regarding LBD and MSA; facilitate the sharing of data, reagents, and resources generated by the U19 Center with other researchers in partnership with the NIA; train the next generation of AD/LBD investigators. In this manner, Core A plays a key role in the Penn U19 Center to foster accomplishment of its mission.